The long-term objective is to develop a general utility instrument capable of inexpensive de novo sequencing that can also be used for re-sequencing projects to recognize genome variation in heterozygous genomes. The system being developed will sequentially, and directly, identify the nucleotides in very long fragments of genomic DNA from a base-dependent electronic signal produced by a nanopore articulated with nanotube probes. The final system is intended to provide a relatively high quality sequence from 6.5-fold coverage of a genome using DNA from fewer than 1 million cells, with no amplification and minimal preparative steps. The specific aims for the initial 5 year period of this project are: 1. Improve nanopore surfaces to reduce nonspecific adsorption, pore clogging, and electrical noise; 2. Fabricate and test a nanopore detector articulated with integrated nanotubes for molecular identification; 3. Investigate and optimize the electronic properties of nanotube-DNA interactions to control DNA translocation, orientation and nucleotide contrast; 4. Develop new enzymatic methods to better control and limit the rate of DNA translocation through articulated nanopores; 5. Develop algorithms for feature detection and identification of signals from articulated nanopores; 6. Demonstrate single base sensitivity and resolution on single-stranded DNA translocating through a nanopore. If, as proposed here, we are able to resolve each base as it passes through a nanopore at the rate of 104 bases/sec, an instrument with an array of 100 such nanopores could produce a high-quality draft sequence of 1 mammalian genome in ~20 hours at a cost of approximately $1,000/mammalian genome. Genomic sequencing at these sharply reduced costs would make vital contributions to improved human health on many fronts, including the understanding, diagnosis, treatment, and prevention of disease; advances in agriculture, environmental science and remediation; and the genetics of human health and disease derived from the understanding of evolution.